OMIM ID:
Mental Retardation, X-Linked 99, Syndromic, Female-Restricted
Alternate Names
Defective Genes
Clinical Characteristics
Ocular Features
Palpebral fissures are generally shortened and may slant up or down. Cataracts of unknown morphology have been reported and strabismus is common.
Systemic Features
The systemic phenotype is highly variable. Skull and facial anomalies are common with brachycephaly, bitemporal narrowing, and a broad low nasal bridge. There is general developmental delay in both motor and cognitive abilities. Patients are short in stature while scoliosis, hip dysplasia, and post-axial polydactyly may be present. The teeth may be malformed and numerous (29%) of individuals have hypertrichosis. Nearly a third of individuals have a cleft palate/bifid uvula. Heart malformations, primarily atrial septal defects, are found in about half of affected individuals and urogenital anomalies such as renal dysplasia are relatively common. Feeding difficulties have been reported while anal atresia is present in about half of patients.
Brain imaging reveals hypoplasia of the corpus callosum, enlarged ventricles, Dandy-Walker malformations, cerebellar hypoplasia, and abnormal gyration patterns in the frontal lobe. Generalized hypotonia has been diagnosed in half of reported patients and seizures occur in 24%.
Genetics
Inheritance
This female-restricted syndrome is caused by heterozygous mutations in the USP9X gene (Xp11.4). X-chromosome inactivation is skewed greater than 90% in the majority of females but the degree of skewing in one study was independent of clinical severity. The majority of cases occur de novo.
In males, hemizygous mutations in the USP9X gene (300919) cause a somewhat similar disorder (MRX99) without the majority of the congenital malformations having mainly the intellectual disabilities, hypotonia, and behavioral problems.
Pedigree
X-linked dominant, mother affected
X-linked inheritance patterns result from mutations located on the X chromosome. Females have two X chromosomes of which only one carries a mutation in X-linked dominant disorders. This usually results in expression of the disease and women with a single mutation have the disorder caused by the mutation. Half of their offspring, male and female, will inherit the mutation. Men, with only one X chromosome, will always have the condition if they inherit the one with the mutation. Men would transmit it to all of their offspring. Without a modifying normal gene on a second X chromosome, X-linked dominant conditions are frequently lethal in such males. The result is a vertical transmission pattern, usually from female to female.
X-linked inheritance patterns result from mutations located on the X chromosome. Females have two X chromosomes of which only one carries a mutation in X-linked dominant disorders. This usually results in expression of the disease and women with a single mutation have the disorder caused by the mutation. Half of their offspring, male and female, will inherit the mutation. Men, with only one X chromosome, will always have the condition if they inherit the one with the mutation. Men would transmit it to all of their offspring. Without a modifying normal gene on a second X chromosome, X-linked dominant conditions are frequently lethal in such males. The result is a vertical transmission pattern, usually from female to female.